Institute of Laboratory Animal Science, CAMS & Comparative Medicine Center, PUMC, Beijing, China.
National Human Diseases Animal Model Resource Center, Beijing, China.
J Neuroinflammation. 2024 Nov 1;21(1):282. doi: 10.1186/s12974-024-03277-3.
The Interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) pathway, along with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, are critical contributors to neuroinflammation in Alzheimer's disease (AD). Although previous research outside the context of AD has indicated that the IL-6-STAT3 pathway may regulate the cGAS-STING pathway, the exact molecular mechanisms through which IL-6-STAT3 influences cGAS-STING in AD are still not well understood.
The activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of 5×FAD and WT mice was analyzed using WB and qRT-PCR. To explore the effects of IL-6 deficiency, Il6 mice were crossed with 5×FAD mice, and the subsequent impact on hippocampal STAT3 pathway activity, cGAS-STING pathway activation, amyloid pathology, neuroinflammation, and cognitive function was evaluated through WB, qRT-PCR, immunohistochemistry, ThS staining, ELISA, and behavioral tests. The regulatory role of STAT3 in the transcription of the Cgas and Sting genes was further validated using ChIP-seq and ChIP-qPCR on hippocampal tissue from 5×FAD and Il6: 5×FAD mice. Additionally, in the BV2 microglial cell line, the impact of STAT3 activation on the transcriptional regulation of Cgas and Sting genes, as well as the production of inflammatory mediators, was examined through WB and qRT-PCR.
We observed marked activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of AD mice, which was attenuated in the absence of IL-6. IL-6 deficiency reduced beta-amyloid deposition and neuroinflammation in the hippocampus of AD mice, contributing to cognitive improvements. Further analysis revealed that STAT3 directly regulates the transcription of both the Cgas and Sting genes. These findings suggest a potential mechanism involving the STAT3-cGAS-STING pathway, wherein IL-6 deficiency mitigates neuroinflammation in AD mice by modulating this pathway.
These findings indicate that the STAT3-cGAS-STING pathway is critical in mediating neuroinflammation associated with AD and may represent a potential therapeutic target for modulating this inflammatory process in AD.
白细胞介素-6（IL-6）-信号转导子和转录激活子 3（STAT3）途径以及环鸟苷酸-腺苷酸合酶（cGAS）-干扰素基因刺激物（STING）途径是阿尔茨海默病（AD）神经炎症的关键贡献者。尽管 AD 以外的先前研究表明，IL-6-STAT3 途径可能调节 cGAS-STING 途径，但 IL-6-STAT3 影响 AD 中 cGAS-STING 的确切分子机制仍不清楚。
使用 WB 和 qRT-PCR 分析 5×FAD 和 WT 小鼠海马中 IL-6-STAT3 和 cGAS-STING 途径的激活。为了探索 IL-6 缺乏的影响，将 Il6 小鼠与 5×FAD 小鼠杂交，然后通过 WB、qRT-PCR、免疫组织化学、ThS 染色、ELISA 和行为测试评估对海马 STAT3 途径活性、cGAS-STING 途径激活、淀粉样蛋白病理学、神经炎症和认知功能的影响。使用 ChIP-seq 和 ChIP-qPCR 进一步验证 STAT3 在 5×FAD 和 Il6:5×FAD 小鼠海马组织中 Cgas 和 Sting 基因转录中的调节作用。此外，在 BV2 小胶质细胞系中，通过 WB 和 qRT-PCR 研究了 STAT3 激活对 Cgas 和 Sting 基因转录调节以及炎症介质产生的影响。
我们观察到 AD 小鼠海马中 IL-6-STAT3 和 cGAS-STING 途径的明显激活，而在没有 IL-6 的情况下则减弱。IL-6 缺乏减少了 AD 小鼠海马中的β-淀粉样蛋白沉积和神经炎症，导致认知改善。进一步分析表明，STAT3 直接调节 Cgas 和 Sting 基因的转录。这些发现表明存在一种潜在的机制，涉及 STAT3-cGAS-STING 途径，其中 IL-6 缺乏通过调节该途径减轻 AD 小鼠的神经炎症。
这些发现表明 STAT3-cGAS-STING 途径在介导与 AD 相关的神经炎症中至关重要，并且可能代表调节 AD 中这种炎症过程的潜在治疗靶点。
